The development of the adequate ligands to effectively hold metals is a critical step for enhancing the efficacy of radioimmunotherapy (RIT) and magnetic resonance imaging (MRI). The long-term objective of the proposed research is to develop clinically viable ligands that have direct applications in two cancer research fields, RIT and MRI. In the current proposal we will focus our effort on two specific aims regarding the design of macrocyclic ligands that may address the pressing needs for active clinical exploration of RIT and MRI. The first specific aim is to explore a bimodal binding approach to generate better bifunctional ligands to efficiently bind promising radionuclides for use in RIT. This aim is based on the hypothesis that the cooperative binding using both a macrocyclic cavity and an acyclic pendant binding group may provide enhanced kinetics in metal complexation while maintaining a high level of complex stability. Our preliminary data indicate that one of the new ligands, NOETA binds Y-86, an important radioactive metal for RIT for the first time, with excellent kinetics and in vivo stability. We will further test the bimodal binding approach by preparing bifunctional ligands for RIT applications, and by evaluating complexation kinetics and thermodynamics of the bifunctional ligands with a variety of radioactive metals for RIT such as Y-90, Bi-213 and Ac-225. The second specific aim is to investigate how incorporation of naturally occurring steroid(s) into the conventional contrast agent affects criteria of tumor-specific MR contrast agents, i.e., high and extended signal intensity, in vivo stability, good cell permeation, complete clearance, and high target specificity. This aim is based on the hypothesis that a steroid moiety incorporated into the conventional MR contrast agent promotes non-covalent interactions between the steroid transporters and the conjugated contrast construct. The new ligand NOETA also has shown MR signal intensity, and in vivo stability comparable to the clinically approved non-specific MRI agents. Using this ligand as a scaffold, we will investigate the potential of the attached steroid as a tumor targeting vector of tumor-specific MR contrast agents. The results of the proposed research will contribute to the development of better drugs for both MRI and RIT, which will greatly enhance clinical exploration of both modalities, and directly benefit cancer patients.